Abstract Current in vitro models of vascularized bone tissues do not mimic the in vivo microenvironment comprising of diverse cell types in communication with each other through stromal barriers. In addition, they are hampered by lack of real-time visualization and quantitation of vasculature-bone as well as bone-cartilage interactions. In contrast, animal models while providing useful information are time consuming, expensive and in recent years, have increasingly raised ethical concerns. Furthermore, animal studies provide limited understanding of mechanistic behavior compared to well-controlled in vitro studies. Thus, there is an unmet need for an in vitro platform for improved monitoring and analysis of vascularized bone-cartilage interactions. We propose to develop and demonstrate a multi-scale model of vascularized bone-cartilage tissue for the understanding of cellular signaling with a Phase I focus on the interactions between endothelial cells, bone cells, specifically osteoblasts (bone-building cells) and osteoclasts (bone-degrading cells), and chondrocytes (cartilage cells). The multi-scale nature of the proposed approach is based on the use of (a) a microscale based vascular bone-cartilage model using microfluidics and tissue engineering to study cell signaling, which informs (b) a meso-scale vascular bone-cartilage model interrogating both engineered constructs and native tissues for structural and functional studies. Phase I will clearly and unequivocally demonstrate the use of this multiscale model of vascularized osteochondral tissue interactions for cell signaling. The developed platform will mimic the morphology, physiological flow and 3D multi-cellular compositions observed in vivo and enable an easy and robust system for evaluation of cellular responses. In Phase II, the platform will be expanded to include other stromal cells (e.g., fibroblasts), and immune cells (e.g., macrophages), followed by detailed characterization of the signaling molecules and therapeutic screening. A multi-disciplinary industry-academic partnership with expertise in microfluidics cell based assays and musculoskeletal biology and tissue regeneration has been assembled for successful completion of this project. By providing an accurate, quantitative and predictive model of physiological interactions, the developed multi-scale platform promises to establish a new paradigm for in vitro assessment of the physiological response to therapeutics.